1. Field of the Invention
The present invention relates to a process for producing 3-amino-2-oxo-1-halogenopropane derivatives which can easily be converted to optically active 3-substituted-3-amino-1,2-epoxypropane derivatives which are equivalents of α-aminoalcohol derivatives that are important as intermediates for HIV protease inhibitors or certain enzyme inhibitors.
2. Discussion of the Background
α-Aminoalcohol derivatives which can easily be converted from optically active 3-substituted-3-amino-1,2-epoxypropane derivatives are used as intermediates for synthesis of a large number of HIV protease inhibitors such as Ro31-8959 (Parkes K. et al (Roche), J. Org. Chem., 1994, vol. 59, p.3656) SC-52151 (Getman D. P. et al. (Monsanto), J. Med. Chem., 1993, Vol. 36, p. 288) VX478 (Verte, WO9405639), and AG1343 (Lilly, WO9521164].
Known examples of a method of producing 3-amino-1, 2-epoxypropane derivatives include a method in which the 2-position of an N-protected-3-amino-2-oxo-1-halogenopropane is reduced stereoselectively to form the corresponding alcohol, and this alcohol is then epoxidized through dehydrohalogenation (Getman D. P. et al., J. Med. Chem., 1993, vol. 36, p. 288), a method in which N-protected-3-amino-1-propene is epoxidized oxidatively asymmetrically (Luly J. R. et al., J. Org. Chem., 1987, vol. 52, p. 1487), and a method in which methylene is inserted into N-protected-3-amino-1-propanal (Searle G. D., WO93/23388.).
In the first method, it is important how the key intermediate N-protected 3-amino-2-oxo-1-halogenopropane or its equivalent substance can be produced industrially at low cost. However, industrialization of this method is limited since it has to use diazomthane having quite a high explosiveness and a strong toxicity as a sub-starting material (see for example, Getman D. P. et al., J. Med. Chem., 1993, vol. 36, p. 288; Okada Y. et al., Chem. Pharm. Bull., 1988 vol. 36, p. 4794; EP 346867;  EP 346847; and Raddatz P. et al., J. Med. Chem., 1991, vol. 34, p. 3267). Further, there is a method in which an N-substituted amino acid ester is reacted with a halomethyl anion. However, quite an unstable halomethyl anion is used, and a halogen to be introduced into the 1-position is presumably limited to chorine or fluorine in view of a common chemical knowledge. For these reasons, industrialization of this method is limited (Barluenga et al., J. Chem. Soc., Chem. Commun., 1994).
Still further, a method in which, after a C-terminus of an N-substituted amino acid is activated, the resulting compound is reacted with fluoromalonic acid half ester for decarboxylation (EP 442754) can be mentioned as a known technology. In this method, however, the halogen is limited to a specific element, fluorine. Therefore, this method cannot be applied to a system containing chlorine or bromine for achieving the object of the present invention.
In the second method, the Wittier reaction of a costly aldehyde (3-amino-1-propanal) is utilized to produce the key intermediate. N-substituted-3-amino-1-propane. Consequently, this method involves quite a high cost. Further, in the third method, not only does the method of forming the intermediate. N-substituted aldehyde entail a high cost, but also carbine has to be formed at a low temperature when inserting methylene. Accordingly, this method is not industrially appropriate.
Thus, there remains a need for a method of preparing compounds which can easily be converted to intermediates useful for preparing HIV proteases. There also remains a need for a need for processes for preparing amino-2-oxo-1-halogenopropane derivatives and 3-amino-1,2-epoxypropane derivatives.